Fumaric acid esters (FAEs) such as dimethyl fumarate are approved in Germany for the treatment of psoriasis, are approved in the United States for the treatment of multiple sclerosis, are being evaluated in the United States for the treatment of psoriasis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions.
FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111 (1), 43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronic obstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US 2007/0027076); cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris (Joshi et al., WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,509,376, U.S. Pat. No. 6,858,750, and U.S. Pat. No. 7,157,423); transplantation (Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 6,359,003, U.S. Pat. No. 6,509,376, and U.S. Pat. No. 7,157,423; and Lehmann et al., Arch Dermatol Res 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, U.S. Pat. No. 6,509,376, U.S. Pat. No. 7,157,423, and US 2006/0205659) including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 and U.S. Pat. No. 6,436,992; Went and Lieberburg, US 2008/0089896; Schimrigk et al., Eur J Neurology 2006, 13, 604-610; and Schilling et al., Clin Experimental Immunology 2006, 145, 101-107); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); advanced glycation end products (AGE)-induced genome damage (Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis; and others (Nilsson et al., WO 2006/037342 and Nilsson and Muller, WO 2007/042034).
The mechanism of action of fumaric acid esters is believed to be mediated by pathways associated with the immunological response. For example, FAEs invoke a shift from a Th1 to Th2 immune response, favorably altering the cytokine profile; inhibit cytokine-induced expression of adhesion molecules such as VCAM-1, ICAM-1 and E-selectin, thereby reducing immune cell extravasation; and deplete lymphocytes through apoptotic mechanisms (Lehmann et al., J Investigative Dermatology 2007, 127, 835-845; Gesser et al., J Investigative Dermatology 2007, 127, 2129-2137; Vandermeeren et al., Biochm Biophys Res Commun 1997, 234, 19-23; and Treumer et al., J Invest Dermatol 2003, 121, 1383-1388).
Recent studies suggest that FAEs are inhibitors of NF-κB activation, a transcription factor that regulates the inducible expression of proinflammatory mediators (D'Acquisto et al., Molecular Interventions 2002, 2 (1), 22-35). Accordingly, FAEs have been proposed for use in treating NF-κB mediated diseases (Joshi et al., WO 2002/055066; and Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. No. 7,157,423 and U.S. Pat. No. 6,509,376). Inhibitors of NF-κB activation have also been shown to be useful in angiostatic therapy (Tabruyn and Griffioen, Angiogenesis 2008, 11, 101-106), inflammatory bowel disease (Atreya et al., J Intern Med 2008, 263 (6), 591-6); and in animal models of diseases involving inflammation including neutrophilic alveolitis, asthma, hepatitis, inflammatory bowel disease, neurodegeneration, ischemia/reperfusion, septic shock, glomerulonephritis, and rheumatoid arthritis (D'Acquisto et al., Molecular Interventions 2002, 2 (1), 22-35).
Studies also suggest that NF-κB inhibition by FAEs may be mediated by interaction with tumor necrosis factor (TNF) signaling. Dimethyl fumarate inhibits TNF-induced tissue factor mRNA and protein expression and TNF-induced DNA binding of NF-κB proteins, and inhibits the TNF-induced nuclear entry of activated NF-κB proteins thereby inhibiting inflammatory gene activation (Loewe et al., J Immunology 2002, 168, 4781-4787). TNF signaling pathways are implicated in the pathogenesis of immune-mediated inflammatory diseases such as rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis (Tracey et al., Pharmacology & Therapetuics 2008, 117, 244-279).
FUMADERM®, an enteric coated tablet containing a salt mixture of ethyl hydrogen fumarate and dimethyl fumarate (DMF) (2), which is rapidly hydrolyzed to methyl hydrogen fumarate (MHF) (1) in vivo and is regarded as the main bioactive metabolite, was approved in Germany in 1994 for the treatment of psoriasis.

FUMADERM® is dosed three times/day with 1-2 grams/day administered for the treatment of psoriasis. FUMADERM® exhibits a high degree of interpatient variability with respect to drug absorption and food strongly reduces bioavailability. Absorption is thought to occur in the small intestine with peak levels achieved 5-6 hours after oral administration. Significant side effects occur in 70-90% of patients (Brewer and Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; and Hoefnagel et al., Br J Dermatology 2003, 149, 363-369). Side effects of current FAEs therapy include gastrointestinal upset including nausea, vomiting, diarrhea, and transient flushing of the skin. Also, DMF exhibits poor aqueous solubility.
Tecfidera™, formerly called BG-12, is a delayed release (i.e., a capsule containing enteric-coated microtablets) oral dosage form of dimethyl fumarate. Tecfidera™ (dimethyl fumarate) was approved in the USA in 2013, and is dosed two times per day with 480 mgs/day administered for the treatment of multiple sclerosis. Details concerning the clinical testing of BG-12 are disclosed in Sheikh et al., Safety Tolerability and Pharmacokinetics of BG-12 Administered with and without Aspirin, Key Findings from a Randomized, Double-blind, Placebo-controlled Trial in Healthy Volunteers, Poster PO4.136 presented at the 64th Annual Meeting of the American Academy of Neurology, Apr. 21-28, 2012, New Orleans, La.; Dawson et al., Bioequivalence of BG-12 (Dimethyl Fumarate) Administered as a Single 240 mg Capsule and Two 120 mg Capsules: Findings from a Randomized, Two-period Crossover Study, Poster P913 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Oct. 10-13, 2012, Lyon, France; and Woodworth et al., Pharmacokinetics of Oral BG-12 Alone Compared with BG-12 and Interferon β-1a or Glatiramer Acetate Administered Together, Studied in Health Volunteers, Poster PO4.207 presented at the 62nd Annual Meeting of the American Academy of Neurology, Apr. 10-17, 2010, Toronto, Ontario, Canada.
Fumaric acid derivatives (Joshi and Strebel, WO 2002/055063, US 2006/0205659, and U.S. Pat. No. 7,157,423 (amide compounds and protein-fumarate conjugates); Joshi et al., WO 2002/055066 and Joshi and Strebel, U.S. Pat. No. 6,355,676 (mono and dialkyl esters); Joshi and Strebel, WO 2003/087174 (carbocyclic and oxacarbocylic compounds); Joshi et al., WO 2006/122652 (thiosuccinates); Joshi et al., US 2008/0233185 (dialkyl and diaryl esters)) and salts (Nilsson et al., US 2008/0004344) have been developed in an effort to overcome the deficiencies of current FAEs therapy. Controlled release pharmaceutical compositions comprising fumaric acid esters are disclosed by Nilsson and Müller, WO 2007/042034. Glycolamide ester prodrugs are described by Nielsen and Bundgaard, J Pharm Sci 1988, 77 (4), 285-298.
Gangakhedkar et al., U.S. Patent Publication No. 2010/0048651, discloses prodrugs of monomethyl fumarate having the following chemical formula:
wherein:R1 and R2 are independently chosen from hydrogen, C1-6 alkyl, and substituted C1-6 alkyl;R3 and R4, together with the nitrogen to which they are bonded, can form a C5-10-heteroaryl ring such as a morpholino ring; and R5 can be hydrogen, methyl, ethyl, and C3-6 alkyl; and pharmaceutical compositions containing such compounds for the treatment of diseases including psoriasis, multiple sclerosis, an inflammatory bowel disease, asthma, chronic obstructive pulmonary disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and arthritis. When R5 is methyl, such compounds are prodrugs of monomethyl fumarate. These glycol amide prodrugs of monomethyl fumarate can be prepared by reacting monomethyl fumarate with a reactant comprising the glycol amide promoiety. In general, the starting monomethyl fumarate can be prepared by isomerization of the corresponding monomethyl maleate.
For example, Guzowski et al., WO2012/170923, discloses preparation of monomethyl fumarate by esterification of fumaric acid with methanol in the presence of sulfuric acid.
Lei et al., Ziyuan Kaifa Yu Shichang (2011), 27 (9), 787-789, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using hydrochloric acid.
Zhao et al., Shipin Gongye Keji (2008), 29 (6), 259-262, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using 2 wt % hydrochloric acid as a catalyst.
Zhang et al., Jingxi Huagong Zhongjianti (2006), 36 (6), 71-72, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using phosphoric acid as a catalyst.
Zheng et al., Huaxue Shijie (2004), 45 (4), 207-208, 217, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using phosphoric acid and AlCl3 as a catalyst.
Gu et al., Faming Zhuanli Shenqing (2010), CN 101774913, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using fumaryl chloride as a catalyst.
Li et al., Faming Zhuanli Shenqing Gongkai Shuomingshu (2005), CN 1616400, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using hydrogen halide as a catalyst.
Takaoka et al., Jpn. Kokai Tokkyo Koho (1991), JP 03294245, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate in the presence of aq. NaBr and aq. K2S2O8.
Ikebe et al., Jpn. Kokai Tokkyo Koho (1985), JP 60181047, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate in the presence of quaternary ammonium bromide and organic peroxide.
Dyicky, Organic Preparations and Procedure International (1983), 15 (4), 233-8, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using HCl, AlCl3, or phthaloyl chloride as a catalyst.
Schweckendiek et al., German Patent (1964) DE 1165586, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using oxalyl chloride as a catalyst.
Spatz, et al., Journal of Organic Chemistry (1958), 23, 1559-60, discloses preparation of monomethyl fumarate via isomerization of monomethyl maleate using thiourea as a catalyst.